Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Am J Physiol Renal Physiol
2010 Dec 01;2996:F1359-64. doi: 10.1152/ajprenal.00257.2010.
Show Gene links
Show Anatomy links
Hypertension resistance polymorphisms in ROMK (Kir1.1) alter channel function by different mechanisms.
Fang L
,
Li D
,
Welling PA
.
???displayArticle.abstract???
The renal outer medullary K(+) (ROMK) channel plays a critical role in renal sodium handling. Recent genome sequencing efforts in the Framingham Heart Study offspring cohort (Ji W, Foo JN, O'Roak BJ, Zhao H, Larson MG, Simon DB, Newton-Cheh C, State MW, Levy D, and Lifton RP. Nat Genet 40: 592-599, 2008) recently revealed an association between suspected loss-of-function polymorphisms in the ROMK channel and resistance to hypertension, suggesting that ROMK activity may also be a determinant of blood pressure control in the general population. Here we examine whether these sequence variants do, in fact, alter ROMK channel function and explore the mechanisms. As assessed by two-microelectrode voltage clamp in Xenopus oocytes, 3/5 of the variants (R193P, H251Y, and T313FS) displayed an almost complete attenuation of whole cell ROMK channel activity. Surface antibody binding measurements of external epitope-tagged channels and analysis of glycosylation-state maturation revealed that these variants prevent channel expression at the plasmalemma, likely as a consequence of retention in the endoplasmic reticulum. The other variants (P166S, R169H) had no obvious effects on the basal channel activity or surface expression but, instead, conferred a gain in regulated-inhibitory gating. As assessed in giant excised patch-clamp studies, apparent phosphotidylinositol 4,5-bisphosphate (PIP(2)) binding affinity of the variants was reduced, causing channels to be more susceptible to inhibition upon PIP(2) depletion. Unlike the protein product of the major ROMK allele, these two variants are sensitive to the inhibitory affects of a G protein-coupled receptor, which stimulates PIP(2) hydrolysis. In summary, we have found that hypertension resistance sequence variants inhibit ROMK channel function by different mechanisms, providing new insights into the role of the channel in the maintenance of blood pressure.
Du,
Characteristic interactions with phosphatidylinositol 4,5-bisphosphate determine regulation of kir channels by diverse modulators.
2004, Pubmed,
Xenbase
Du,
Characteristic interactions with phosphatidylinositol 4,5-bisphosphate determine regulation of kir channels by diverse modulators.
2004,
Pubmed
,
Xenbase
Ecelbarger,
Regulation of potassium channel Kir 1.1 (ROMK) abundance in the thick ascending limb of Henle's loop.
2001,
Pubmed
Fang,
The ARH adaptor protein regulates endocytosis of the ROMK potassium secretory channel in mouse kidney.
2009,
Pubmed
Flagg,
A mutation linked with Bartter's syndrome locks Kir 1.1a (ROMK1) channels in a closed state.
1999,
Pubmed
,
Xenbase
Flagg,
Molecular mechanism of a COOH-terminal gating determinant in the ROMK channel revealed by a Bartter's disease mutation.
2002,
Pubmed
,
Xenbase
Greger,
Presence of luminal K+, a prerequisite for active NaCl transport in the cortical thick ascending limb of Henle's loop of rabbit kidney.
1981,
Pubmed
Hebert,
Calcium and salinity sensing by the thick ascending limb: a journey from mammals to fish and back again.
2004,
Pubmed
Huang,
Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gbetagamma.
1998,
Pubmed
,
Xenbase
Ji,
Rare independent mutations in renal salt handling genes contribute to blood pressure variation.
2008,
Pubmed
Kifor,
The Ca2+-sensing receptor (CaR) activates phospholipases C, A2, and D in bovine parathyroid and CaR-transfected, human embryonic kidney (HEK293) cells.
1997,
Pubmed
Leung,
Phosphatidylinositol 4,5-bisphosphate and intracellular pH regulate the ROMK1 potassium channel via separate but interrelated mechanisms.
2000,
Pubmed
,
Xenbase
Lopes,
Alterations in conserved Kir channel-PIP2 interactions underlie channelopathies.
2002,
Pubmed
,
Xenbase
Lu,
Absence of small conductance K+ channel (SK) activity in apical membranes of thick ascending limb and cortical collecting duct in ROMK (Bartter's) knockout mice.
2002,
Pubmed
Ma,
An andersen-Tawil syndrome mutation in Kir2.1 (V302M) alters the G-loop cytoplasmic K+ conduction pathway.
2007,
Pubmed
,
Xenbase
O'Connell,
Phosphorylation-regulated endoplasmic reticulum retention signal in the renal outer-medullary K+ channel (ROMK).
2005,
Pubmed
,
Xenbase
Riccardi,
Physiology and pathophysiology of the calcium-sensing receptor in the kidney.
2010,
Pubmed
Rohács,
Distinct specificities of inwardly rectifying K(+) channels for phosphoinositides.
1999,
Pubmed
,
Xenbase
Schwalbe,
Potassium channel structure and function as reported by a single glycosylation sequon.
1995,
Pubmed
Schwalbe,
Functional consequences of ROMK mutants linked to antenatal Bartter's syndrome and implications for treatment.
1998,
Pubmed
Simon,
Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK.
1996,
Pubmed
Wang,
Phospholipase A2 is involved in mediating the effect of extracellular Ca2+ on apical K+ channels in rat TAL.
1997,
Pubmed
Wang,
Cytochrome P-450 metabolites mediate extracellular Ca(2+)-induced inhibition of apical K+ channels in the TAL.
1996,
Pubmed
Welling,
A comprehensive guide to the ROMK potassium channel: form and function in health and disease.
2009,
Pubmed
Yoo,
Cell surface expression of the ROMK (Kir 1.1) channel is regulated by the aldosterone-induced kinase, SGK-1, and protein kinase A.
2003,
Pubmed
,
Xenbase
Yoo,
Assembly and trafficking of a multiprotein ROMK (Kir 1.1) channel complex by PDZ interactions.
2004,
Pubmed
,
Xenbase
Yoo,
A phosphorylation-dependent export structure in ROMK (Kir 1.1) channel overrides an endoplasmic reticulum localization signal.
2005,
Pubmed
,
Xenbase
